EP0240874A1 - Préparation de l'hymécromone à résorption élevée et son procédé de préparation - Google Patents

Préparation de l'hymécromone à résorption élevée et son procédé de préparation Download PDF

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Publication number
EP0240874A1
EP0240874A1 EP87104600A EP87104600A EP0240874A1 EP 0240874 A1 EP0240874 A1 EP 0240874A1 EP 87104600 A EP87104600 A EP 87104600A EP 87104600 A EP87104600 A EP 87104600A EP 0240874 A1 EP0240874 A1 EP 0240874A1
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EP
European Patent Office
Prior art keywords
polyoxyethylene
hymecromone
polyoxiethylene
preparation
polyalkylene glycol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP87104600A
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German (de)
English (en)
Other versions
EP0240874B1 (fr
Inventor
Manfred Chem. Löhner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dolorgiet GmbH and Co KG
Original Assignee
Dolorgiet GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dolorgiet GmbH and Co KG filed Critical Dolorgiet GmbH and Co KG
Priority to AT87104600T priority Critical patent/ATE56359T1/de
Publication of EP0240874A1 publication Critical patent/EP0240874A1/fr
Application granted granted Critical
Publication of EP0240874B1 publication Critical patent/EP0240874B1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to a highly absorbable form of preparation of the hymecromon, a method for producing the same and its use for producing capsules, preferably soft gelatin capsules.
  • the compound hymecromone, 7-hydroxy-4-methyl-coumarin is e.g. from Martindale, The Extra Pharmacopoeia, 28th edition, 1982, p. 651 known as a drug that has bile secretion-promoting and biliary-antispasmodic properties. It is used for the treatment of functional disorders in the liver-bile area, particularly in the case of convulsions and dyskinesias of the biliary tract, as well as for functional complaints after interventions in the area of the biliary tract. The complaints mentioned are often acute and are often associated with severe pain.
  • a drug that is suitable for combating acute complaints requires a rapid onset of action, which in turn can only be achieved by rapid release and good bioavailability of the active ingredient. So far, Hymecromon for enteral administration is only available in solid form as coated tablets or tablets.
  • Hymecromon is almost insoluble in cold and warm water (Beilstein's Handbook of Organic Chemistry, 4th ed. 1934, vol. 18, p. 32), making absorption in the aqueous environment of the stomach very difficult.
  • high demands must be placed on the physical Properties of the active ingredient, such as particle size and specific surface area.
  • the manufacturing conditions of the tablets and dragee cores must be strictly observed, since even small changes in the production process, such as mixing, pressing pressure or machine type, influence the physical properties of the active ingredient particles and impair the bioavailability.
  • the object of the invention was first of all to provide an easily ingestible medicament which contains an effective amount of hymecromone in a carrier, which is simple to prepare and quickly develops a high level of effectiveness.
  • Hymecromon is a little in some physiologically compatible solvents, the sodium salt is readily soluble in water.
  • aqueous media e.g. Gastric juice
  • the hymecromon fails immediately, whereby the formation of coarse crystals is promoted by the incorporation of water of crystallization. If such a solution gets into the stomach when taken orally, the aqueous and acidic contents of the stomach cause crystallization of the hmyecromon, which is thus prevented from rapid absorption.
  • Polyalkylene glycols in particular include polyethylene glycol and / or polypropylene glycol, the molar masses being in the range between 200 and 1000, preferably even in the range between 200 and 630.
  • Polyoxyethylene-polyoxypropylene polymer is also suitable, the molar mass range of which should be between 1400 and 2000.
  • This polyalkylene glycol also has the property of acting as a surfactant, so that it may even be possible to dispense with the addition of further surfactants.
  • surfactants are polyoxyethylene glycerol tri-hydroxystearate, polyoxyethylene (C 12-18 ) fatty alcohol ether, polyoxyethylene stearate, polyoxyethylene sorbitan mono- (C 12-18 ) fatty acid ester, sodium dioctyl sulfosuccinate or mixtures thereof.
  • the ethylene oxide units of the polyoxyethylene glycerol tri-hydroxistearate are preferably between 35 and 65, those of the polyoxyethylene (C 12-18 ) fatty alcohol ether between 15 and 25, the ethylene oxide units of the polyoxyethylene stearate between 15 and 45 and those of the polyoxiethylene sorbitan mono - (C12-18 ⁇ fatty acid ester between 15 and 25.
  • the hymecromone is present in the preparations according to the invention in amounts of 20 to 45 parts by weight of active ingredient and 55 to 80 parts by weight of the mixtures.
  • 20 to 45 parts by weight of hymecromone mostly 55 to 80 parts by weight of the polyalkylene glycol and optionally up to 2 parts by weight of 1,2-propanediol are added.
  • 20 to 45 parts by weight of hymecromone are dissolved in 25 to 65 parts by weight of the polyalkylene glycol, preferably polyethylene glycol, 5 to 30 parts by weight of surfactant or surfactants and up to 2 parts by weight of 1,2-propanediol.
  • the active ingredient is incorporated into the mixture at temperatures of 60 to 80 ° C. and converted into a non-crystalline form.
  • the decisive factor here is that part of the hymecromon remains dissolved when it cools to room temperature and that the undissolved part does not return to its original crystal form. It has also been found that when these suspensions are introduced into aqueous media, in particular artificial gastric juice, there is no recrystallization, so that the hymecromon can be rapidly and completely absorbed from this suspension.
  • the suspensions can also be incorporated into capsules, preferably soft gelatin capsules, in a manner known per se. This dosage form has the advantage over all previously known dosage forms of the Hymecromon that the active ingredient is rapidly absorbed after ingestion.
  • the hymecromon When carrying out the process according to the invention, the hymecromon is incorporated into the mixture at 60 to 80 ° C., where it either completely dissolves and partially fails again on cooling to room temperature. It has also been observed that it may even be sufficient to stir the active ingredient in the mixture intensively at from 60 to 80 ° C. for some time in order to convert it into a non-crystalline suspension.
  • the solvent-surfactant mixtures are prepared beforehand by homogeneously mixing the constituents at temperatures up to 100.degree.
  • the present invention thus initially relates to the highly absorbable preparation forms according to claims 1 to 6 above and the process for producing the same according to claims 7 to 12. Finally, the invention relates to the use of the preparations according to claims 1 to 5 for the production of capsules, preferably soft gelatin capsules.
  • 1.050 g suspension contain 400 mg hymecromone.
  • a suspension is prepared from 57.35 g of polyoxyethylene-polyoxypropylene polymer 1900, 1.45 g of 1,2-propanediol, 6.20 g of polyoxyethylene (40) glycerol tri-hydroxystearate, 5.00 g of sodium -dioctyl sulfosuccinate and 20.00 g hymecromone.
  • 0.900 g suspension contain 200 mg hymecromone.
  • a suspension is prepared from 57.35 g of polyethylene glycol 200, 1.45 g of 1,2-propanediol, 6.20 g of polyoxyethylene (40) glycerol tri-hydroxystearate and 40.00 g of hymecromone.
  • 1.050 g suspension contain 400 mg hymecromone.
  • Example 2 Analogously to Example 1, a suspension is produced from 28.675 g of polyethylene glycol 400, 28.67 g of polyoxyethylene-polyoxypropylene polymer 1900, 1.45 g of 1,2-propanediol and 40.00 g of hymecromone.
  • Example 2 Analogously to Example 1, a suspension is prepared from 57.35 g of polyoxiethylene-polyoxypropylene polymer 1900, 1.45 g of 1,2-propanediol and 40.00 g of hymecromone.
  • Example 2 Analogously to Example 1, a suspension is produced from 57.35 g of polyoxiethylene-polyoxypropylene polymer 1900, 1.45 g of 1,2-propanediol and 20.00 g of hymecromone.
  • 0.788 g suspension contain 200 mg hymecromone.
  • Example 2 Analogously to Example 1, a suspension is produced from 57.35 g of polyoxiethylene-polyoxypropylene polymer 1900, 1.45 g of 1,2-propanediol, 6.20 g of polyoxyethylene (30) stearate and 40.00 g of hymecromone.
  • 1.050 g suspension contain 400 mg hymecromone.
  • Example 2 Analogously to Example 1, a suspension is produced from 57.35 g of polyoxiethylene-polyoxypropylene polymer 1900, 1, 45 g 1,2-propanediol, 6.20 Polyoxiethylen- (20) -stearylalkohol g and 40.00 g of hymecromone.
  • 1.050 g suspension contain 400 mg hymecromone.
  • Example 2 Analogously to Example 1, a suspension is prepared from 57.35 g of polyoxiethylene-polyoxypropylene polymer 1500, 1.45 g of 1,2-propanediol, 6.20 g of polyoxyethylene (20) sorbitan monostearate and 40.00 g of Hyemcromon.
  • 1.050 g suspension contain 400 mg hymecromone.
  • a suspension is prepared from 57.35 g of polyoxiethylene-polyoxypropylene polymer 2000, 1.45 g of 1,2-propanediol, 6.20 g of polyoxyethylene (60) glycerol tri-hydroxystearate and 40.00 g of hymecromone .
  • 1.050 g suspension contain 400 mg hymecromone.
  • a suspension is prepared from 57.35 g of polyoxyethylene-polyoxypropylene polymer 1900, 1.45 g of 1,2-propanediol, 6.20 g of sodium dioctyl sulfosuccinate and 40.00 g of hymecromone.
  • 1.050 g suspension contain 400 mg hymecromone.
  • a suspension is prepared analogously to Example 2 from 57.35 g of polyethylene glycol 400, 1.45 g of 1,2-propanediol, 6.20 g Polyoxiethylen- (40) -glycerol-tri-hydroxy stearate, 5, 00 g of sodium dioctyl sulfosuccinate and 40.00 g hymecromon.
  • the release of the hymecromon from the preparations according to the invention was checked by means of a dissolution test according to USP XX, 5th supplement (paddle method), in 900 ml of artificial gastric juice according to USP XX without pepsin at 36.5 ° C.
  • the rotation speed of the stirrer was 100 rpm.
  • the release medium was continuously pumped through a glass frit (G3) fitted with a filter by means of a peristaltic pump through the flow cell of a Beckman spectrophotometer, model DU-7, and back into the release vessel.
  • the concentration of the hymecromon was determined at the wavelength of 257 nm.
  • the mean values given in the table were calculated from 6 individual measurements each.
  • the bioavailability of the hymecromone from the capsules according to the invention and a commercially available dragee was tested in five test subjects.
  • the test subjects were given a capsule or dragee with 400 mg Hymecromon each.
  • Blood was drawn from the test subjects before and after 0.25, 0.5, 1, 2, 3 and 4 hours.
  • Plasma was obtained from the blood by centrifugation with the addition of ethylenediaminotetraacetic acid.
  • hymecromon is conjugated quickly with glucuronic or sulfuric acid, so that the conjugates appear in the plasma in addition to free (non-conjugated) hymecromon.
  • Table 2 shows that the capsules according to the invention improved the bioavailability of the hymecromone by up to 51% compared to the commercially available dragee.
  • the capsules according to the invention have a faster flooding of the active ingredient than in the previously known preparation. With the faster and higher release and bioavailability of hymecromon from the capsules according to the invention, a better and faster-acting medicinal product containing hymecromon is available than hitherto.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
EP87104600A 1986-04-05 1987-03-27 Préparation de l'hymécromone à résorption élevée et son procédé de préparation Expired - Lifetime EP0240874B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT87104600T ATE56359T1 (de) 1986-04-05 1987-03-27 Hochresorbierbare zubereitungsform des hymecromons und verfahren zur herstellung derselben.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3611467 1986-04-05
DE19863611467 DE3611467A1 (de) 1986-04-05 1986-04-05 Hochresorbierbare zubereitungsform des hymecromons und verfahren zur herstellung derselben

Publications (2)

Publication Number Publication Date
EP0240874A1 true EP0240874A1 (fr) 1987-10-14
EP0240874B1 EP0240874B1 (fr) 1990-09-12

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EP87104600A Expired - Lifetime EP0240874B1 (fr) 1986-04-05 1987-03-27 Préparation de l'hymécromone à résorption élevée et son procédé de préparation

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EP (1) EP0240874B1 (fr)
JP (1) JPS62255424A (fr)
AT (1) ATE56359T1 (fr)
DE (2) DE3611467A1 (fr)
ES (1) ES2018186B3 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021550A1 (fr) * 1997-10-24 1999-05-06 Bio-Monde Preparations Limited Utilisation d'anticoagulants coumariniques pour le traitement des troubles du tube digestif

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2764581B2 (ja) * 1988-04-05 1998-06-11 東洋カプセル株式会社 腸内拡散の速い新規ピコスルファートナトリウム製剤
DE19545043A1 (de) * 1995-12-02 1997-06-05 Scherer Gmbh R P Pharmazeutische Präparate zur oralen Anwendung und Verfahren zu ihrer Herstellung
US6294192B1 (en) * 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3175943A (en) * 1961-07-13 1965-03-30 Lipha Process for stimulating choleresis
DE2700085A1 (de) * 1976-07-13 1978-01-26 Lipha Arzneimittel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3175943A (en) * 1961-07-13 1965-03-30 Lipha Process for stimulating choleresis
DE2700085A1 (de) * 1976-07-13 1978-01-26 Lipha Arzneimittel

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021550A1 (fr) * 1997-10-24 1999-05-06 Bio-Monde Preparations Limited Utilisation d'anticoagulants coumariniques pour le traitement des troubles du tube digestif
US6407073B1 (en) 1997-10-24 2002-06-18 Bio-Monde Preparations Limited Use of coumarin derivatives for the treatment of digestive tract disorders

Also Published As

Publication number Publication date
ATE56359T1 (de) 1990-09-15
DE3611467A1 (de) 1987-10-08
DE3764843D1 (de) 1990-10-18
ES2018186B3 (es) 1991-04-01
EP0240874B1 (fr) 1990-09-12
JPS62255424A (ja) 1987-11-07

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